Delta-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it.

ABSTRACT

A δ-crystalline form of ivabradine hydrochloride of formula (I): 
     
       
         
         
             
             
         
       
     
     characterised by its powder X-ray diffraction data. 
     Medicinal products containing the same which are useful as bradycardics.

The present invention relates to the δ-crystalline form of ivabradinehydrochloride of formula (I)

to a process for its preparation and to pharmaceutical compositionscontaining it.

Ivabradine, and addition salts thereof with a pharmaceuticallyacceptable acid, and more especially its hydrochloride, have veryvaluable pharmacological and therapeutic properties, especiallybradycardic properties, making those compounds useful in the treatmentor prevention of various clinical situations of myocardial ischaemiasuch as angina pectoris, myocardial infarct and associated rhythmdisturbances and also in various pathologies involving rhythmdisturbances, especially supraventricular rhythm disturbances, and inheart failure.

The preparation and therapeutic use of ivabradine and addition siltsthereof with a pharmaceutically acceptable acid, and more especially itshydrochloride, have been described in the European patent specificationEP 0 534 859.

In view of the pharmaceutical value of this compound, it has been ofprime importance to obtain it with excellent purity. It has also beenimportant to be able to synthesise it by means of a process that canreadily be converted to the industrial scale, especially in a form thatallows rapid filtration and drying. Finally, that form had to beperfectly reproducible, easily formulated and sufficiently stable toallow its storage for long periods without particular requirements fortemperature, light or oxygen level.

The patent specification EP 0 534 859 describes a synthesis process forivabradine and its hydrochloride. However, that document does notspecify the conditions for obtaining ivabradine in a form that exhibitsthose characteristics in a reproducible manner.

The Applicant has now found that a particular salt of ivabradine, thehydrochloride, can be obtained in a well defined crystalline form thatexhibits valuable characteristics for stability and processability.

More specifically, the present invention relates to the δ-crystallineform of ivabradine hydrochloride, characterised by the following powderX-ray diffraction diagram, measured using a PANalytical X'Pert Prodiffractometer together with an X'Celerator detector and expressed interms of line position (Bragg's angle 2 theta, expressed in degrees),line height (expressed in counts), line area (expressed in counts xdegrees), line width at half-height (“FWHM”, expressed in degrees) andinterplanar distance d (expressed in Å):

Angle 2 theta Height Area (counts FWHM Interplanar Line no. (degrees)(counts) x degrees) (degrees) distance (Å) 1 4.1 1115 110 0.1004 21.7532 6.8 183 145 0.8029 12.907 3 8.4 755 75 0.1004 10.531 4 10.9 1104 1280.1171 8.087 5 12.2 195 19 0.1004 7.268 6 14.3 569 75 0.1338 6.214 714.7 1847 274 0.1506 6.013 8 15.3 1734 315 0.184 5.802 9 16.3 1164 1540.1338 5.442 10 16.8 3420 734 0.2175 5.269 11 17.5 790 78 0.1004 5.06912 17.9 3389 503 0.1506 4.960 13 19.2 2467 407 0.1673 4.635 14 19.8 14529 0.2007 4.477 15 20.4 313 52 0.1673 4.362 16 21.2 928 169 0.184 4.19817 21.7 2093 414 0.2007 4.099 18 22.2 3850 635 0.1673 4.007 19 22.5 57676 0.1338 3.948 20 23.1 1588 236 0.1506 3.855 21 24.8 1665 247 0.15063.594 22 25.2 1212 120 0.1004 3.534 23 25.6 1507 249 0.1673 3.477 2426.7 2042 303 0.1506 3.342 25 27.6 2281 414 0.184 3.229 26 28.4 485 960.2007 3.138 27 29.6 599 99 0.1673 3.014

The invention relates also to a process for the preparation of theδ-crystalline form of ivabradine hydrochloride, which process ischaracterised in that acetonitrile or a mixture of acetonitrile andwater is preheated, ivabradine hydrochloride is added, the solutionobtained is allowed to cool at room temperature, held at roomtemperature until crystallisation is complete, and the crystals formedare collected.

-   -   In the crystallisation process according to the invention it is        possible to use ivabradine hydrochloride obtained by any        process, for example ivabradine hydrochloride obtained by the        preparation process described in patent specification EP 0 534        859.    -   The solution may advantageously be seeded during the cooling        step.    -   The acetonitrile or mixture of acetonitrile and water is        preferably preheated to a temperature between 60° C. and reflux,        more preferably between 65 and 75° C.    -   The dilution is preferably more than 15 ml/g, more preferably        between 50 and 100 ml/g.

The invention relates also to pharmaceutical compositions comprising asactive ingredient the δ-crystalline form of ivabradine hydrochloridetogether with one or more appropriate, inert and non-toxic excipients.Among the pharmaceutical compositions according to the invention theremay be mentioned, more especially, those that are suitable for oral,parenteral (intravenous or subcutaneous) or nasal administration,tablets or dragées, sublingual tablets, capsules, lozenges,suppositories, creams, ointments, dermal gels, injectable preparationsand drinkable suspensions.

The useful dosage can be varied according to the nature and severity ofthe disorder, the administration route and the age and weight of thepatient. The dosage varies from 1 to 500 mg per day in one or moreadministrations.

The Examples that follow illustrate the invention.

The X-ray powder diffraction spectrum was measured under the followingexperimental conditions:

-   -   PANalytical X'Pert Pro diffractometer, X'Celerator detector,        temperature-regulated chamber,    -   voltage 45 kV, intensity 40 mA,    -   mounting θ-θ,    -   nickel (Kβ) filter,    -   incident-beam and diffracted-beam Soller slit: 0.04 rad,    -   automatic divergence slits: irradiated length of 10 mm,    -   mask: 10 mm,    -   antiscatter slit: ½°,    -   measurement mode: continuous from 30 to 30°, in increments of        0.017°,    -   measurement time per step: 19.7 s,    -   total time: 4 min 32 s,    -   measurement speed: 0.108°/s,    -   measurement temperature: ambient.

EXAMPLE 1 δ-Crystalline Form of Ivabradine Hydrochloride

160 ml of acetonitrile are preheated to 70° C. and then 2 g ofivabradine hydrochloride obtained according to the process described inpatent specification EP 0 534 859 are added, in portions, with stirringuntil dissolution is complete. The solution is then stored at ambienttemperature for 2 days. The crystals are removed by filtration in vacuoand are spread out onto a crystallisation plate.

The water content of the product obtained, determined by coulometry, is2.8%.

Powder X-Ray Diffraction Diagram:

The powder X-ray diffraction profile (diffraction angles) of the δ-formof ivabradine hydrochloride is given by the significant lines collatedin the following table:

Angle 2 theta Height Area (counts FWHM Interplanar Line no. (degrees)(counts) x degrees) (degrees) distance (Å) 1 4.1 1115 110 0.1004 21.7532 6.8 183 145 0.8029 12.907 3 8.4 755 75 0.1004 10.531 4 10.9 1104 1280.1171 8.087 5 12.2 195 19 0.1004 7.268 6 14.3 569 75 0.1338 6.214 714.7 1847 274 0.1506 6.013 8 15.3 1734 315 0.184 5.802 9 16.3 1164 1540.1338 5.442 10 16.8 3420 734 0.2175 5.269 11 17.5 790 78 0.1004 5.06912 17.9 3389 503 0.1506 4.960 13 19.2 2467 407 0.1673 4.635 14 19.8 14529 0.2007 4.477 15 20.4 313 52 0.1673 4.362 16 21.2 928 169 0.184 4.19817 21.7 2093 414 0.2007 4.099 18 22.2 3850 635 0.1673 4.007 19 22.5 57676 0.1338 3.948 20 23.1 1588 236 0.1506 3.855 21 24.8 1665 247 0.15063.594 22 25.2 1212 120 0.1004 3.534 23 25.6 1507 249 0.1673 3.477 2426.7 2042 303 0.1506 3.342 25 27.6 2281 414 0.184 3.229 26 28.4 485 960.2007 3.138 27 29.6 599 99 0.1673 3.014

EXAMPLE 2 Pharmaceutical Composition

Formula for the preparation of 1000 tablets each containing 5 mg ofivabradine base:

Compound of Example 1 5.39 g Maize starch 20 g Anhydrous colloidalsilica 0.2 g Mannitol 63.91 g PVP 10 g Magnesium stearate 0.5 g

1. A δ-Crystalline form of ivabradine hydrochloride of formula (I):


2. The δ-Crystalline form of ivabradine hydrochloride of claim 1 havinga powder X-ray diffraction diagram exhibiting peaks at 16.8, 17.9, 19.2,22.2 and 27.6 deg 2 theta.
 3. The δ-Crystalline form of ivabradinehydrochloride of claim 1 having a powder X-ray diffraction diagramexhibiting peaks at 4.1, 8.4 and 10.9 deg 2 theta.
 4. A pharmaceuticalcomposition comprising as active ingredient the δ-crystalline form ofivabradine hydrochloride of claim 1, in combination with one or morepharmaceutically acceptable, inert, non-toxic carriers.
 5. A method fortreating or preventing a condition requiring a bradycardic, such methodcomprising the step of administering to a living animal body, includinga human, a therapeutically effective amount of a δ-crystalline form ofivabradine hydrochloride of claim
 1. 6. A method for treating orpreventing clinical situations of myocardial ischaemia and/or acondition involving rhythm disturbances, such method comprising the stepof administering to a living animal body, including a human, atherapeutically effective amount of the δ-crystalline form of ivabradinehydrochloride of claim
 1. 7. The method of claim 6, wherein the clinicalsituation of myocardial ischaemia is selected form angina pectoris,myocardial infarct and associated rhythm disturbances.
 8. The method ofclaim 6, wherein the condition involving rhythm disturbances is selectedfrom supraventricular rhythm disturbances and heart failure.